Regional and cell type-specific variations in tonic GABAergic inhibition.
BACKGROUND: The diversity of GABAA receptor subunits and their configurations during
subunit assembly produce a variety of receptors with different functional properties.
Variations in subcellular localization, GABA binding affinity, and pore kinetics give
rise to two classes of GABAergic conductance—phasic and tonic—with
heterogeneity across brain regions and cell types. The precis... read moree roles of tonic versus
phasic GABAergic signaling are only beginning to be uncovered. METHODS: Here we used a
novel floxed Gabrd mouse model to selectively remove the extrasynaptic delta
subunit–containing receptors that mediate tonic inhibition from specific cell
types, and studied the impact from the cellular level to circuits to behavior in
physiological and pathological contexts. RESULTS: Three areas of investigation were
explored: (1) Removal of the delta subunit from excitatory principal neurons was
expected to increase neuronal excitability and result in greater susceptibility to
pharmacologically induced seizures. However, dentate gyrus granule cells proved
resistant to complete removal of the delta subunit, suggesting the importance of tonic
inhibition in controlling hippocampal excitability. (2) Removal of tonic inhibition from
interneurons of the hippocampus resulted in greater inhibitory drive onto principal
neurons. This suppression of hippocampal excitability produced a phenotype that showed
protection against seizures, but also exhibited deficits in learning and memory. (3)
Tonic GABAergic conductance in CRH neurons of the paraventricular nucleus in the
hypothalamus plays a role in modulating the body's physiological response to stress.
Because the chloride gradient is flipped during acute stress, removing the delta subunit
from CRH neurons blunted the release of corticosterone and diminished stress-related
behaviors. CONCLUSIONS: Taken together, our studies have sampled a bit of the variety in
the roles of tonic GABAergic conductance across brain regions and cell types. Further
experiments with other genetic tools will allow greater focus into more specific cell
types and neural circuits. The floxed Gabrd mouse should prove a useful tool for future
Thesis (Ph.D.)--Tufts University, 2016.
Submitted to the Dept. of Neuroscience.
Advisor: Jamie Maguire.
Committee: Chris Dulla, Stephen Moss, and Leon Reijmers.
Keyword: Neurosciences.read less